JP2021521280A - Compositions and Methods for Treating Elastic Fibrosis - Google Patents

Abstract

The present disclosure relates to pharmaceutical compositions capable of regulating elastic fibers. The present disclosure further relates to methods of treating elastic fiber-related disorders such as COPD by inhalation of low molecular weight hyaluronic acid. [Selection diagram] None

Description

Related Applications This application claims the priority benefit of US Provisional Patent Application No. 62 / 656,654 filed April 12, 2018, the contents of which are incorporated herein by reference in their entirety.

Background The protease-antiprotease concept of lung interstitial injury has encouraged the use of elastase inhibitors as a potential treatment for chronic obstructive pulmonary disease (COPD). However, with the exception of α-1 antiprotease (AAP) replacement therapy for AAP-deficient patients, this approach has been largely unsuccessful, and clinical trials of various inhibitors have failed to produce successful drugs for COPD. There is.

Description of the Invention In the present disclosure, at least in part, inhalation of the long-chain polysaccharide hyaluronan (HA) preferentially binds to pulmonary elastic fibers, prevents elastic fiber degradation, and dilates the airspace in an experimental model of emphysema. Based on the discovery of limiting. Thus, in certain embodiments, the present disclosure provides a method of treating elastic fiber-related disorders by administering a dose of low molecular weight hyaluronic acid inhalation solution.

In one aspect, a pharmaceutical composition comprising hyaluronic acid or a pharmaceutically acceptable salt thereof having a weight average molecular weight (M _{w) of about 50 to about 1000 kDa; and a pharmaceutically acceptable excipient is provided.} .. In another aspect, an inhaler comprising the pharmaceutical compositions described herein is provided. Yet another embodiment treats an elastic fiber-related disorder in a subject, comprising administering to the subject hyaluronic acid having a weight average molecular weight (M _{w) of about 50 to about 1000 kDa or a pharmaceutically acceptable salt thereof.} A method for is provided.

Figure 1 shows the tapering of plasma DID levels after treatment with HA (r = -0.98; p = 0.02). Data are expressed as mean ± SEM. Abbreviations: DID, desmosine and isodesmosine; SEM, standard error of mean.

Figure 2 shows a statistically significant negative correlation between sputum DID levels and time after treatment with HA (r = -0.97; p = 0.03). Data are expressed as mean ± SEM. Abbreviations: DID, desmosine and isodesmosine; SEM, standard error of mean.

Detailed Description of the Invention In the present disclosure, upon inhalation, the long-chain polysaccharide hyaluronan (HA) preferentially binds to pulmonary elastic fibers, prevents elastic fiber degradation, and limits the expansion of the airspace in an experimental model of emphysema. Is at least partially based on the discovery. Desmosine and isodesmosine (DID) levels in plasma, sputum, and urine are measured systemically as markers of elastin degradation in the lung and also as markers of inflammation and fibrinogen.

The results of the study in Example 1 show that aerosol administration of a 0.01% solution of low molecular weight HA was well tolerated and did not contain adverse events requiring discontinuation of treatment. In addition, a significant reduction in DID levels in plasma and sputum was observed, suggesting that nebulized HA may protect elastin fibers from degradation and thus limit the development of emphysema. ing. Compared to recent studies involving long-term administration of AAP in patients with chronic obstructive pulmonary disease (COPD) with AAP deficiency, the reduction in plasma levels of DID in this study was greater and occurred more rapidly. The continued decrease in both plasma and sputum DID levels for the first week after discontinuation reflects the binding of HA to elastic fibers, which far exceeds its half-life in the lungs. And last.

Aerosolated fluorescein-labeled HA (molecular weight 150 kDa) is capable of entering the alveoli and preferentially binds to alveolar wall elastic fibers, which probably interferes with interaction with harmful substances such as elastase and oxidants. There is a theory.

Aerosolized preparations of HA compounds may be used as therapeutic aerosols for certain upper respiratory tract disorders, but have not been tested for efficacy in other diseases or disorders such as COPD. HA has also been used in patients with cystic fibrosis as an additive to hypertonic saline therapy. The HA used in these treatments is prepared in high molecular weight form (300-1,000 kDa). Low molecular weight forms of HA, such as 150 kDa HA, have lower viscosities and can achieve lower aerosol particle diameters, thereby causing elastic fibers in the peripheral lung (its destruction is a central feature of emphysema). There is a theory that facilitates their access to.

While there are many animal studies showing pro-inflammatory events associated with low molecular weight HA, this finding is generally associated with pre-existing acute lung injury and is associated with COPD-related chronic and subacute inflammatory processes. It cannot be considered representative. In addition, the clinical trials described herein show no evidence of HA-induced inflammation, and long-term treatment of smoke-exposed animals with aerosolized HA is either bronchoalveolar lavage fluid or lung tissue sections. , Did not show an increase in white blood cell count.

HA may be effective against a variety of damaging substances involved in the pathogenesis of the disease, as elastic fiber degradation may be the ultimate common pathway in COPD. In contrast to other proposed treatments such as certain elastase inhibitors, HA may provide broader protection of the lungs with a lower potential for side effects. Furthermore, the generally slow progression of alveolar wall injury in COPD suggests that even a slight reduction in elastic fiber injury can significantly reduce the risk of respiratory failure.

Thus, in certain embodiments, the present disclosure provides a method of treating elastic fiber-related disorders, for example by administering a dose of low molecular weight hyaluronic acid, eg, as an inhalation solution.

Elastic fibers (or yellow fibers) are bundles of proteins (elastin) found in the extracellular matrix of connective tissue and are produced by arterial smooth muscle cells and fibroblasts. Elastic fibers include elastin, elastin and oxytalan. Elastic tissue is classified as "proprietary connective tissue". Elastic fibers are formed from elastic microfibrils (consisting of numerous proteins such as microfibril-related glycoproteins, fibrillin, fibrillin, and elastin receptors) and amorphous elastin. Elastic fibers are found in skin, lungs, arteries, veins, intrinsic connective tissue, elastic cartilage, periodontal ligament, fetal tissue and other structures.

Non-limiting examples of elastic fiber-related disorders include cutis laxa, Marfan's syndrome, α-1 antitrypsin deficiency (elastin excessively degrades elastin), emphysema, chronic obstructive pulmonary disease (COPD), and liver. Diseases, Bushke-Orendorf Syndrome, Menquez's Disease, Elastic Fibrous Pseudo-Emphysema, Marfan Syndrome, Harler's Disease, Hypertension and Congenital Heart Defects.

In some embodiments, a pharmaceutical composition comprising hyaluronic acid or a pharmaceutically acceptable salt thereof having a weight average molecular weight (M _{w) of about 50 to about 1000 kDa; and a pharmaceutically acceptable excipient is provided.} Will be done.

Numerous embodiments are further provided that can be applied to any aspect of the present disclosure. For example, in some embodiments, hyaluronic acid is about 50 kDa, about 60 kDa, about 70 kDa, about 80 kDa, about 90 kDa, about 100 kDa, about 110 kDa, about 120 kDa, about 130 kDa, about 140 kDa, about 150 kDa, about 160 kDa, about 170kDa, about 180kDa, about 190kDa, about 200kDa, about 210kDa, about 220kDa, about 230kDa, about 240kDa, about 250kDa, about 260kDa, about 270kDa, about 280kDa, about 290kDa, about 300kDa, about 400kDa, about 500kDa, about 600kDa, _{It has a weight average molecular weight (M w} ) of about 700 kDa, about 800 kDa, about 900 kDa, and / or about 1000 kDa. In some embodiments, hyaluronic acid is 50-900 kDa, 50-800 kDa, 50-700 kDa, 50-600 kDa, 50-500 kDa, 50-400 kDa, 50-300 kDa, 50-290 kDa, 50-280 kDa, 50-270 kDa. , 50-260kDa, 50-250kDa, 50-240kDa, 50-230kDa, 50-220kDa, 50-210kDa, 50-200kDa, 50-190kDa, 50-180kDa, 50-170kDa, 50-160kDa, 50-150kDa, 50 _{It has a weight average molecular weight (M w} ) of ~ 140 kDa, 50 ~ 130 kDa, 50 ~ 120 kDa, 50 ~ 110 kDa, or 50-100 kDa. In some embodiments, hyaluronic acid has a weight average molecular weight (M _w ) of about 150 kDa.

In some embodiments, the pharmaceutical compositions described herein are inhalable forms. In some embodiments, the pharmaceutical compositions described herein are in a form suitable for intranasal, intrapulmonary, intratracheal, intrabronchial, or intraalveolar administration. In some embodiments, the pharmaceutical compositions described herein are suitable forms for intra-alveolar administration. In some embodiments, the pharmaceutical compositions described herein are in a form suitable for administration by a dry powder inhaler. In some embodiments, the pharmaceutical compositions described herein are in a form suitable for administration by a liquid sprayer. In some embodiments, the liquid sprayer is an aerosol device. In some embodiments, the aerosol device is a nebulizer or electrohydrodynamic aerosol device.

In some embodiments, an inhaler comprising the pharmaceutical compositions described herein is provided.

Numerous embodiments are further provided that can be applied to any aspect of the present disclosure. For example, in some embodiments, the inhalers described herein are 0.1-5 μm, 0.1-4 μm, 0.1-3 μm, 0.1-2 μm, 0.1-1 μm, 1-5 μm, 1-4 μm, 1-3 μm. , 1-2 μm, 2-5 μm, 2-4 μm, 2-3 μm, 3-5 μm, 3-4 μm, or 4-5 μm sized droplets are configured to be delivered. In some embodiments, the inhalers described herein are about 0.1 μm, about 0.2 μm, about 0.3 μm, about 0.4 μm, about 0.5 μm, about 0.6 μm, about 0.7 μm, about 0.8 μm, about. It is configured to deliver droplets of size 0.9 μm, about 1 μm, about 1.5 μm, about 2 μm, about 2.5 μm, about 3 μm, about 3.5 μm, about 41 μm, about 4.5 μm, or about 5 μm. In some embodiments, the inhalers described herein are configured to deliver droplets with a size of 2 μm to 3 μm.

In some embodiments, for treating elastic fiber-related disorders in a subject, including administering to the subject hyaluronic acid having a weight average molecular weight (M _{w) of 50-1000 kDa or a pharmaceutically acceptable salt thereof.} The method is provided.

Numerous embodiments are further provided that can be applied to any aspect of the present disclosure. For example, in some embodiments, hyaluronic acid is about 50 kDa, about 60 kDa, about 70 kDa, about 80 kDa, about 90 kDa, about 100 kDa, about 110 kDa, about 120 kDa, about 130 kDa, about 140 kDa, about 150 kDa, about 160 kDa, about 170kDa, about 180kDa, about 190kDa, about 200kDa, about 210kDa, about 220kDa, about 230kDa, about 240kDa, about 250kDa, about 260kDa, about 270kDa, about 280kDa, about 290kDa, about 300kDa, about 400kDa, about 500kDa, about 600kDa, _{It has a weight average molecular weight (M w} ) of about 700 kDa, about 800 kDa, about 900 kDa, and / or about 1000 kDa. In some embodiments, hyaluronic acid is 50-900 kDa, 50-800 kDa, 50-700 kDa, 50-600 kDa, 50-500 kDa, 50-400 kDa, 50-300 kDa, 50-290 kDa, 50-280 kDa, 50-270 kDa. , 50-260kDa, 50-250kDa, 50-240kDa, 50-230kDa, 50-220kDa, 50-210kDa, 50-200kDa, 50-190kDa, 50-180kDa, 50-170kDa, 50-160kDa, 50-150kDa, 50 _{It has a weight average molecular weight (M w} ) of ~ 140 kDa, 50 ~ 130 kDa, 50 ~ 120 kDa, 50 ~ 110 kDa, or 50-100 kDa. In some embodiments, hyaluronic acid has a weight average molecular weight (M _w ) of about 150 kDa. In some embodiments, the methods described herein include administering hyaluronic acid by inhalation. In some embodiments, the methods described herein include administering hyaluronic acid to the sinuses, lung system, trachea, bronchi, or alveoli. In some embodiments, elastic fiber-related disorders include cutis laxa, Williams syndrome, alpha-1 antitrypsin deficiency, emphysema, chronic obstructive pulmonary disease (COPD), liver disease, Buschke-Ollendorff syndrome, Menkes disease, Elastic fibrous pseudoxanthoma, Marfan syndrome, Harler's disease, hypertension or congenital heart defects. In some embodiments, the elastic fiber-related disorder is COPD.

Pharmaceutical Compositions The compositions and methods of the present disclosure can be utilized to treat individuals in need thereof. In certain embodiments, the individual is a mammal, such as a human, or a non-human mammal. When administered to animals such as humans, the composition or compound preferably comprises, for example, a compound of the present disclosure (eg, hyaluronic acid of the appropriate molecular weight disclosed herein) and a pharmaceutically acceptable carrier. It is administered as a pharmaceutical composition. Pharmaceutically acceptable carriers are well known in the art and are, for example, aqueous solutions such as water or physiologically buffered saline, or other solvents or vehicles (eg, glycols, glycerol, oils (eg, glycols, glycerol, oils, etc.)). , Olive oil), or injectable organic esters). In a preferred embodiment, the aqueous solution is pyrogen-free or substantially pyrogen-free when such pharmaceutical compositions are for human administration, especially for invasive routes of administration. Excipients can be selected, for example, to result in delayed release of the drug or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in the form of a dosage unit such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophils for reconstruction, powders, aerosols, solutions, syrups, suppositories, injections and the like. .. The composition may also be present in a transdermal delivery system, eg, a skin patch. The composition is also administered by inhalation such that it is sprayed into the nose, absorbed (nasally) through the nasal membrane and / or inhaled into the lungs through the mouth (by inhalation) or through the mouth and nose (by nebulizer). May be present in a suitable solution.

A pharmaceutically acceptable carrier is a physiologically acceptable agent that acts to stabilize a compound, such as the compounds of the present disclosure, increase its solubility, or increase its absorption. May include. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. Contains agents. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) can also be a liposome or other polymeric matrix, for example, the compounds of the present disclosure can be incorporated therein. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers that are relatively easy to make and administer.

The phrase "pharmaceutically acceptable" is used herein, within the correct medical judgment, of humans and animals without excessive toxicity, irritation, allergic reactions, or other problems or complications. It is used to refer to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with tissues and that are commensurate with a reasonable benefit / risk ratio.

"Pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be compatible with the other ingredients of the formulation and "acceptable" in the sense that it is not harmful to the patient. Some examples of materials that can act as pharmaceutically acceptable carriers are: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) Excipients such as cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered traganth; (5) malt; (6) gelatin; (7) talc; (8) cocoa butter and suppository wax. Agents; (9) oils such as peanut oil, cotton seed oil, benivana oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) glycols such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) Esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide, aluminum hydroxide; (15) alginic acid; (16) exothermic water-free water; 17) Isotonic saline; (18) Ringer's solution; (19) Ethyl alcohol; (20) Starch buffer; and (21) Other non-toxic compatible substances used in pharmaceutical formulations.

The pharmaceutical composition (preparation) can be administered to the subject by any of many routes of administration, eg, oral (eg, aqueous or non-aqueous solution or suspension, tablets, capsules (sprinkle capsules and gelatin capsules). (Including), bolus, powder, granules, paste for application to the tongue); absorption through the oral mucosa (eg, sublingual); subcutaneous; transdermal (eg, as a patch applied to the skin); and topical Includes (eg, as a cream, ointment or spray applied to the skin). The compounds may also be formulated for inhalation. In certain embodiments, the compound may simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable for the same can be found, for example, in U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896 and the patents cited therein. be able to.

The formulation can conveniently be present in the unit dosage form and can be prepared by any method well known in the field of pharmacy. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will generally be the amount of compound that produces a therapeutic effect. Generally, of 100 percent, this amount ranges from about 0.001 percent to about 99 percent of the active ingredient, preferably from about 0.01 percent to about 0.05 percent, and most preferably from about 0.01 percent to about 0.03 percent.

The method of preparing these formulations or compositions comprises the step of associating an active compound (eg, a compound of the present disclosure) with a carrier and optionally one or more auxiliary components. Generally, a pharmaceutical product is prepared by uniformly and intimately associating the compounds of the present disclosure with a liquid carrier, / or a fine solid support, and then, if necessary, molding the product.

In addition to the active compound, the powder and spray can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. The spray may also include chlorofluorohydrocarbons and custom propellants such as volatile unsubstituted hydrocarbons such as butane and propane.

As used herein, the terms "parenteral administration" and "parenteral administration" usually mean, but are not limited to, venous administration modes other than enteral and topical administration by injection. Intra, intraocular (intravitreal, etc.), intramuscular, intraarterial, intrathecal, intracapsular, intraocular, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepithelial, intraarticular Includes (intraarticular), subcapsular, subarachnoid, intrathecal and intrathoracic injections and infusions. A pharmaceutical composition suitable for parenteral administration is one or more pharmaceutically acceptable sterile isotonic or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile injectable solutions immediately prior to use. Or a solute or suspension that contains one or more active compounds in combination with a sterile powder that can be reconstituted into a dispersion and makes the formulation isotonic with the blood of the intended recipient, such as antioxidants, buffers, bacteriostatic agents. It may contain a turbulent or thickener.

Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol), and suitable mixtures thereof, vegetable oils (such as olive oil). , As well as injectable organic esters (such as ethyl oleate). Proper fluidity can be maintained, for example, by using coating materials, maintaining the required particle size in the case of dispersants, and using surfactants.

These compositions may also include adjuvants such as preservatives, wetting agents, emulsifying agents and dispersants. Prevention of microbial activity may be guaranteed by including, for example, various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol sorbate. It is also desirable to include isotonic agents such as sugar and sodium chloride in the composition. In addition, inclusion of agents that delay absorption, such as aluminum monostearate and gelatin, can result in long-term absorption of injectable pharmaceutical forms.

In some cases, it is desirable to delay the absorption of the drug from subcutaneous or intramuscular injections in order to prolong the effect of the drug. This can be achieved by using a liquid suspension of a crystalline or amorphous material with low water solubility. In that case, the rate of absorption of the drug may depend on its rate of dissolution, which in turn may depend on its crystal size and crystal morphology. Alternatively, delayed absorption of the orally administered drug form is achieved by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are made by forming a microencapsulated matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. The rate of drug release can be adjusted depending on the ratio of the drug to the polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly (orthoester) and poly (anhydride). Depot injection formulations are also prepared by capturing the drug in liposomes or microemulsions that are compatible with body tissue.

For use in the methods provided in the present disclosure, the active compound itself or, for example, in combination with 0.01-99.5% (more preferably 0.5-90%) of the active ingredient in combination with a pharmaceutically acceptable carrier. Can be provided as a pharmaceutical composition comprising.

The introduction method may also be provided by a rechargeable or biodegradable device. In recent years, various sustained release polymer devices have been developed and tested in vivo for controlled delivery of drugs, including proteinaceous biopharmacy. Various biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form implants for sustained release of the compound at a particular target site.

The actual dose level of the active ingredient in the pharmaceutical composition is not toxic to the patient and obtains the amount of active ingredient effective in achieving the desired therapeutic response for a particular patient, composition, and mode of administration. Can be changed as

The dose level selected is the specific compound or combination of compounds used, or the activity of its ester, salt or amide, route of administration, duration of administration, rate of excretion of the specific compound used, duration of treatment, use. Other drugs, compounds and / or materials used in combination with certain compounds to be treated, age, gender, weight, condition, general health and previous medical history of the patient being treated, and similar well known in the medical field. Depends on various factors, including those of

A physician or veterinarian in the art can readily determine and prescribe a therapeutically effective amount of the required pharmaceutical composition. For example, a physician or veterinarian may start a dose of a pharmaceutical composition or compound at a lower level than required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. Can be made to. "Therapeutic effective amount" means the concentration of a compound sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of a compound varies according to the subject's weight, gender, age, and medical history. Other factors affecting the effective dose include the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent administered with the compounds of the present disclosure. However, it is not limited to these. Multiple doses of the drug can deliver a larger total dose. Methods of determining efficacy and dosage are known to those of skill in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, incorporated herein by reference).

In general, a suitable daily dose of active compound used in the compositions and methods of the present disclosure is the amount of compound that is the lowest effective dose to produce a therapeutic effect. Such effective doses generally depend on the factors mentioned above.

If desired, the effective daily dose of active compound is 1, 2, 3, 4, 5, 6 or more subdivided, administered separately at appropriate intervals throughout the day, optionally in unit dosage forms. It may be administered as a dose. In certain embodiments of the present disclosure, the active compound may be administered twice or three times daily. In a preferred embodiment, the active compound is administered once daily.

Patients receiving this treatment are any animal in need of it, including primates, especially humans; and other mammals such as horses, cows, pigs, sheep, cats, and dogs; poultry; Includes pets in general.

In certain embodiments, the compounds of the present disclosure may be administered alone or in combination with another type of therapeutic agent.

The disclosure includes the use of pharmaceutically acceptable salts of the compounds of the present disclosure in the compositions and methods of the present disclosure. In certain embodiments, the intended salts of the present disclosure include, but are not limited to, alkyl, dialkyl, trialkyl or tetraalkylammonium salts. In certain embodiments, the intended salts of the present disclosure include L-arginine, benenthamine, benzatin, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2- (diethylamino) ethanol, ethanolamine, Ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4- (2-hydroxyethyl) morpholine, piperazine, potassium, 1- (2-hydroxyethyl) pyrrolidine, sodium, triethanolamine Includes, but is not limited to, amines, tromethamines, and zinc salts. In certain embodiments, the intended salts of the present disclosure include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts. In certain embodiments, the intended salts of the present disclosure are 1-hydroxy-2-naphthoic acid, 2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-amino. Salicylic acid, acetic acid, adipic acid, l-ascorbic acid, l-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-shonoic acid, (+)-campar-10-sulfonic acid, capric acid (decanoic acid), capron Acid (hexanoic acid), capric acid (octanoic acid), carbonic acid, silicic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactalic acid, gentidine Acids, d-glucoseptonic acid, d-gluconic acid, d-glucuronic acid, glutamic acid, glutaric acid, glycerophosphate, glycolic acid, horse uric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, Maleic acid, l-apple acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitrate, oleic acid, oxalic acid, palmitic acid, pamoic acid , Phosphoric acid, propionic acid, l-pyrroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, l-tartrate acid, thiocyan acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylate, but these Not limited to.

Pharmaceutically acceptable acid addition salts can also exist as various solvates such as water, methanol, ethanol, dimethylformamide and the like. A mixture of such solvates can also be prepared. Such solvates can be obtained from crystallization solvents and can be inherent in the solvent for preparation or crystallization, or incidental to such solvents.

Wetting agents such as sodium lauryl sulfate and magnesium stearate, emulsifiers and lubricants, as well as colorants, release agents, coatings, sweeteners, flavors and fragrances, preservatives and antioxidants are also included in the composition. May exist in.

Examples of pharmaceutically acceptable antioxidants are (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bicarbonate, sodium metabisulfite, and sodium sulfite; (2) ascorbic palmitate, butyl. Oil-soluble antioxidants such as hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol; and (3) citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartrate, Examples include metal chelating agents such as phosphoric acid.

In certain embodiments, a container in which the present disclosure holds a therapeutically effective amount of a compound of the present disclosure alone or in combination with a second drug and one or more symptoms of the disease or disorder intended in the present disclosure. It is intended for packaged pharmaceutical compositions, including instructions for using the compound for treatment, prevention, or mitigation.

The formulation can be used as a mixture with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier materials suitable for any suitable mode of administration known in the art. The pharmaceutical product is sterilized and, if desired, auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts to affect osmotic buffers, colorants, fragrances and / or aromas. It may be mixed with a substance or the like. They can also be combined with other activators (eg, analgesics) if desired.

Routes of administration of any of the compositions of the present disclosure include nasal, inhalation, intratracheal, intrapulmonary, intrabronchial, and inhalation.

Suitable compositions and dosage forms include, for example, dispersions, suspensions, solutions, syrups, granules, beads, powders, pellets, nasal or liquid sprays for oral administration, dry powders or aerosols for inhalation. Examples include formulations. It should be understood that the formulations and compositions useful in the present disclosure are not limited to the particular formulations and compositions described herein.

The powder formulation and the granule formulation of the pharmaceutical preparation of the present disclosure can be prepared by using a known method. Such formulations can be administered directly to the subject and can be used, for example, to form materials suitable for administration to the subject. Each of these formulations may further contain one or more dispersants or wetting agents, suspending agents, preservatives. Additional excipients such as fillers and sweeteners, flavoring agents, or colorants may also be included in these formulations.

The pharmaceutical composition of the present disclosure can be prepared, packaged, or sold as a preparation suitable for pulmonary administration via the buccal oral cavity. Such compositions contain the active ingredient and can include dry particles having a diameter in the range of about 0.5 to about 7 nanometers, and in certain embodiments from about 1 to about 6 nanometers. Such compositions either use a device containing a dry powder reservoir to which the flow of propellant is directed to conveniently disperse the powder, or are dissolved or suspended in a low boiling point propellant in a closed container. It is a form of dry powder for administration using a self-injection solvent / powder dosing container such as an apparatus containing the active ingredient. In certain embodiments, such powders comprise particles, where at least 98% by weight of the particles have a diameter greater than 0.5 nanometers, and at least 95% of the particles have a diameter of less than 7 nanometers. Have. In certain embodiments, at least 95% by weight of the particles have a diameter greater than 1 nanometer, and at least 90% of the number of particles have a diameter less than 6 nanometers. The dry powder composition may comprise a solid fine powder diluent such as sugar and is conveniently provided in unit dosage form.

Low boiling point propellants generally include liquid propellants having a boiling point of less than 65 ° F at atmospheric pressure. In general, the propellant can make up 50-99.9% (w / w) of the composition and the active ingredient can make up 0.1-20% (w / w) of the composition. The propellant may further comprise additional ingredients such as a liquid nonionic or solid anionic surfactant or solid diluent (having the same particle size as the particles containing the active ingredient in certain embodiments).

The pharmaceutical compositions of the present disclosure formulated for pulmonary delivery may also provide the active ingredient in the form of droplets of a solution or suspension. Such formulations can be prepared, packaged, or sold as optionally sterile, aqueous or dilute alcohol solutions or suspensions containing the active ingredient and are conveniently administered using a nebulizer or atomizer device. be able to. Such formulations are one or more additions containing, but not limited to, flavoring agents such as sodium saccharin, volatile oils, buffers, surfactants, or preservatives such as methyl hydroxybenzoate. It may further contain a target component. In certain embodiments, the droplets provided by this route of administration have an average diameter in the range of about 0.1 to about 200 nanometers. In some embodiments, the droplets provided by this route of administration are 0.1-5 μm, 0.1-4 μm, 0.1-3 μm, 0.1-2 μm, 0.1-1 μm, 1-5 μm, 1-4 μm, 1-4 μm in diameter. Appropriate amounts of droplets of 3 μm, 1-2 μm, 2-5 μm, 2-4 μm, 2-3 μm, 3-5 μm, 3-4 μm, or 4-5 μm (eg, described elsewhere herein). As such, it contains a sufficient amount of droplets) to deliver a therapeutically effective amount to the target tissue. In certain embodiments, the route of administration is about 0.1 μm, about 0.2 μm, about 0.3 μm, about 0.4 μm, about 0.5 μm, about 0.6 μm, about 0.7 μm, about 0.8 μm, about 0.9 μm, about 1 μm, It provides an appropriate amount of droplets having a diameter of about 1.5 μm, about 2 μm, about 2.5 μm, about 3 μm, about 3.5 μm, about 41 μm, about 4.5 μm, or about 5 μm. In certain embodiments, this route of administration provides an appropriate amount of droplets with a diameter of about 2 μm to about 3 μm.

The pharmaceutical compositions of the present disclosure can be delivered using an inhaler as described in US Pat. No. 8,333,192 B2. This patent is incorporated herein by reference in its entirety.

The present disclosure provides methods for delivering the drug deeper into the lungs and for delivering the drug to lung targets of the drug, including bronchioles and alveoli. The agent is intended to include any particle, molecule or composition administered to the subject, human or animal to achieve any desired result. For example, the aerosolized drug can be administered to the patient's respiratory tract, where the patient can be any animal or human subject. In some embodiments, the aerosolized surfactant is administered to the patient's respiratory tract, facilitating delivery of the aerosolized agent of the first step to the lung target of the agent. Throughout this specification, the term "particle" or "particle" is administered to a mixture containing a drug or surfactant, droplets in which the drug or surfactant is dissolved, a solid drug or surfactant particle, and a patient. It is intended to include any other composition for which it is intended by those skilled in the art to contain such agents or surfactants. Particles or droplets adhere on the surface of the lumen. The location of the particles depends on the characteristics of the inhaler and the technique of the patient. The patient can then inhale a dose of aerosolized surfactant from the second inhaler. The same effect can be obtained by filing a tandem inhaler, or any other application that allows delivery of smaller particles containing the drug.

The composition may also be administered directly to the lungs by inhalation. Any suitable inhaler is used, eg, the inhaler disclosed in Tong et al., U.S. Pat. No. 6,251,941; Clark et al., U.S. Pat. No. 6,655,379 (these are incorporated herein by reference). obtain. For administration by inhalation, the composition can be conveniently delivered to the lungs by a number of different devices. For example, using a metered dose inhaler (“MDI”) utilizing a canister containing a suitable low boiling point propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. , The composition can be delivered directly to the lungs. MDI devices are available from many suppliers such as 3M Corporation, Aventis, Boehringer Ingleheim, Forest Laboratories, Glaxo-Wellcome, Schering Plough and Vectura.

Alternatively, a dry powder inhaler (DPI) device can be used to administer the composition to the lungs (for suitable inhalers, eg, Raleigh et al., Proc. Amer. Assoc. Cancer Research Annual Meeting, 1999, 40,397 (this). Is incorporated herein by reference)). DPI devices typically use a mechanism such as gas ejection to create a cloud of dry powder within the container, which can then be inhaled by the patient. DPI devices are also well known in the art and can be purchased from many vendors, including, for example, Fisons, Glaxo-Wellcome, Inhale Therapeutic Systems, ML Laboratories, Qdose, and Vectura. A common variation is a multidose DPI (“MDDPI”) system that allows delivery of multiple therapeutic doses. MDDPI devices are available from companies such as AstraZeneca, GlaxoWellcome, IVAX, Schering Plough, Skye Pharma and Vectura. For example, gelatin capsules and cartridges for use in inhalers or insufflators are formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch for these systems. You may.

Another type of device that can be used to deliver the composition to the lungs is, for example, a liquid sprayer supplied by Aradigm Corporation. The liquid spray system can use a very small nozzle hole to aerosolize the liquid drug formulation and then inhale it directly into the lungs.

In some preferred embodiments, a nebulizer device is used to deliver the composition to the lungs. Nebulizers produce aerosols from liquid drug formulations, for example by using ultrasonic energy to form particles that can be easily inhaled (eg, Verschoyle et al., British J. Cancer, 1999, 80, Suppl 2). , 96 (see reference herein). Examples of nebulizers include Sheffield / Systemic Pulmonary Delivery Ltd. (Armer et al., U.S. Pat. No. 5,954,047; van der Linden et al., U.S. Pat. No. 5,950,619; van der Linden et al., U.S. Pat. No. 5,970,974. See)), devices supplied by Aventis and Batelle Pulmonary Therapeutics.

In some preferred embodiments, an electrohydrodynamic (“EHD”) aerosol device is used to deliver the composition to the lungs. The EHD aerosol device uses electrical energy to aerosolize a liquid drug solution or suspension (eg, Noakes et al., US Pat. No. 4,765,539; Coffee, US Pat. No. 4,962,885; Coffee, US Pat. No. 6,105,877; Coffee, US Pat. No. 6,105,571; Coffee, PCT application, WO 95/26234, Coffee, PCT application, WO 95/26235, Coffee, PCT application, WO 95/32807 (these are referenced herein). See)). The electrochemical properties of the composition formulation can be an important parameter for optimizing the delivery of this drug to the lungs using an EHD aerosol device, and such optimizations are routinely performed by those skilled in the art. It is said. EHD aerosol devices can deliver drugs to the lungs more efficiently than existing lung delivery techniques. Other suitable methods of intrapulmonary delivery of the composition are within the scope of the present disclosure.

Liquid drug formulations suitable for use with nebulizers and liquid sprayers as well as EHD aerosol devices typically include compositions with pharmaceutically acceptable carriers. Preferably, the pharmaceutically acceptable carrier is a liquid, such as alcohol, water, polyethylene glycol or perfluorocarbon. Optionally, another material may be added to alter the aerosol properties of the solution or suspension of the composition. Preferably, the material is a liquid such as alcohol, glycol, polyglycol or fatty acid. Other methods of prescribing liquid drug solutions or suspensions suitable for use in aerosol devices are known to those of skill in the art (eg, Biesalski, US Pat. No. 5,112,598; Biesalski, US Pat. No. 5,556,611 (these). Is incorporated herein by reference)).

In certain embodiments, the compositions of the invention are levothyroxine sodium hydrate; _{lactose particles containing lactose H 2} O, gelatin and corn starch; sodium starch glycolate; magnesium stearate; as well as purified talc and colloidal dioxide. Includes a stable dry powder blend containing talc silicified containing silicon. In other embodiments, the dry powder comprises an amount of 4-0.02 mg of levothyroxine sodium per 100 mg of dry powder. In yet another embodiment, the dry powder comprises an amount of lactose greater than 90 mg per 100 mg of dry powder preparation. In yet another embodiment, the dry powder _{comprises lactose particles consisting of lactose H 2} O, gelatin and corn starch, where _{the weight ratio of "lactose H 2} O": "gelatin": "corn starch" is 55-. It is 75: 0.20 to 0.80: 20 to 40. In yet another embodiment, the dry powder comprises an amount of 4-8 mg of sodium starch glycolate per 100 mg of dry powder. In yet another embodiment, the dry powder comprises 0.5-2 mg of magnesium stearate per 100 mg of dry powder. In yet another embodiment, the dry powder comprises 2 mg of talc silica per 100 mg of dry powder, the talc silica contains talc silica and colloidal silicon dioxide, 0.667 mg of purified talc and 1.333 mg of colloidal dioxide for 2 mg of talc silica. Included in the amount of silicon. In yet other embodiments, the blend further comprises a rake. In yet another embodiment, the dry powder comprises an amount of 5-6 mg of sodium starch glycolate per 100 mg of dry powder. In yet another embodiment, the dry powder comprises 1 mg of magnesium stearate per 100 mg of dry powder.

The formulations described herein as useful for pulmonary delivery are also useful for intranasal delivery of the pharmaceutical compositions of the present disclosure.

Another formulation suitable for intranasal administration is a coarse powder containing the active ingredient and having an average particle size of about 0.2-500 μm. Such formulations are administered in the form of snuffing, i.e., by rapid inhalation through the nasal cavity from a container of powder held near the nostrils. Formulations suitable for nasal administration may include, for example, an active ingredient from a minimum of about 0.1% (w / w) to a maximum of 100% (w / w), and one or more of them are described herein. May include additional ingredients that are present.

For convenience of definition , some terms used herein, in the examples and in the appended claims are summarized here.

As used herein, the singular forms "a", "an" and "The" are intended to include the plural unless explicitly stated to be out of context. Further, to the extent that the terms "include", "include", "have", "have" or variations thereof are used in any of the detailed description and / or claims, such terms are terms. It is intended to be as inclusive as "contains". The transition term "consisting of" and any grammatical variations thereof are intended to be limited to the elements described in the claims and exclude the elements not described in the claims. The phrase "consisting essentially" and any grammatical variations thereof include embodiments in which the claims include specific elements and substantially affect the basic and novel features of the claims. Indicates that it contains additional elements that do not reach.

The term "about" or "almost" means within an acceptable margin of error for a particular value as determined by one of ordinary skill in the art, which means how the value is measured or determined. That is, it depends in part on the limits of the measurement system and the conventional variability allowed in the art for related parameters.

Unless otherwise defined herein, the scientific and technical terms used in this application shall have meanings commonly understood by those skilled in the art. In general, the chemistry, cell and tissue cultures, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics and proteins as described herein and The nomenclature and techniques used in connection with nucleic acid chemistry are well known and commonly used in the art.

Unless otherwise indicated, the methods and techniques of the present disclosure are described in accordance with conventional methods well known in the art and in various general and more specific references cited and discussed throughout this specification. It is generally performed as it is. For example, "Principles of Neural Science", McGraw-Hill Medical, New York, NY (2000); Motulsky, "Intuitive Biostatistics", Oxford University Press, Inc (1995); Lodish et al., "Molecular Cell Biology, 4th ed." , WHFreeman & Co, New York (2000); Griffiths et al., "Introduction to Genetic Analysis, 7th ed.", WHFreeman & Co., NY (1999); and Gilbert et al., "Developmental Biology, 6th, Sinauer Associates, Inc." ., Sunderland, MA (2000).

Chemical terms used herein are exemplified by "the McGraw-Hill Dictionary of Chemical Terms", Parker S, ed., McGraw-Hill, San Francisco, CA (1985), unless otherwise defined herein. As such, it is used according to conventional use in the art.

All of the above, and any other publications, patents and published patent applications mentioned in this application, are specifically incorporated herein by reference. In case of conflict, the specification containing that particular definition shall prevail.

The term "agent" is used herein to refer to chemical compounds (organic or inorganic compounds, mixtures of chemical compounds, etc.), biological polymers (eg, nucleic acids, antibodies (parts thereof, and humanized, etc.)). Biological materials such as (including chimeric and human antibodies and monoclonal antibodies), proteins or parts thereof (eg, peptides, lipids, carbohydrates, etc.), or bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. Used to indicate an extract made from. Drugs include, for example, drugs whose structure is known and drugs whose structure is unknown.

"Patient," "subject," or "individual" are used interchangeably and refer to either humans or non-human animals. These terms include mammals such as humans, primates, domestic animals (including cows, pigs, etc.), companion animals (eg dogs, cats, etc.) and rodents (eg mice and rats).

To "treat" a condition or patient is to take steps to obtain beneficial or desired outcomes, including clinical outcomes. As used herein and well understood in the art, "treatment" is an approach for obtaining beneficial or desired outcomes, including clinical outcomes. Relieving or ameliorating one or more symptoms or conditions with beneficial or desired clinical outcomes, reducing the degree of disease, stabilizing (ie, not exacerbating) the disease, preventing the spread of the disease, delaying the progression of the disease or It can include, but is not limited to, slowing down, ameliorating or alleviating the disease state, and remission (whether manifestable or undetectable) (whether partial or total). "Treatment" can also mean prolonging survival compared to what would be expected if untreated.

The term "prevent" is recognized in the art and is associated with conditions such as local recurrence (eg, pain), diseases such as cancer, complex syndromes such as heart failure, or any other medical condition. When used in the art, it is well understood in the art to reduce or delay the onset of symptoms of a medical condition in a subject as compared to a subject to which the composition is not administered. Includes administration of the composition. Thus, cancer prevention may include, for example, reducing the number of detectable cancer growth in a population of patients receiving prophylactic treatment compared to an untreated control population, and / or eg statistically and / or A clinically significant amount involves delaying the appearance of detectable cancer growth in the treated population relative to the untreated control population.

"Administration" of a substance, compound or drug to a subject or "administration" of a substance, compound or drug to a subject can be performed using one of a variety of methods known to those of skill in the art. For example, a compound or drug can be intravenous, intraarterial, intradermal, intramuscular, intraperitoneal, subcutaneous, intraocular, sublingual, oral (by ingestion), intranasal (by inhalation), spinal cord, intrabrain, and trans. It can be administered through the skin (eg, by absorption through the skin canal). The compound or drug can also be properly introduced by a rechargeable or biodegradable polymer device or other device (eg, patch and pump, or formulation), which is an extended, slow, extended, slow, compound or drug. Or provide a controlled release. Administration can also be performed, for example, once, multiple times, and / or over one or more extended periods.

As used herein, the phrase "conjoint administration" is such that a second agent is administered while the previously administered therapeutic agent is still effective in the body. Refers to the administration of any form of one or more different therapeutic agents (eg, two agents are effective in a patient at the same time and may include a synergistic effect of the two agents). For example, different therapeutic compounds can be administered simultaneously or in succession, either in the same formulation or in separate formulations. Thus, individuals undergoing such treatment can benefit from the combined effects of different therapeutic agents.

A "therapeutic effective amount" or "therapeutic effective dose" of a drug or drug is the amount of drug or drug that has the intended therapeutic effect when administered to a subject. The complete therapeutic effect is not always manifested by a single dose, but may only be manifested by a series of doses. Therefore, a therapeutically effective amount can be administered in one or more doses. The exact effective amount required for a subject depends, for example, on the size, health and age of the subject, and the nature and extent of the condition being treated, such as cancer or MDS. One of ordinary skill in the art can easily determine the effective amount for a given situation by routine experimentation.

As used herein, the term "regulate" includes inhibition or inhibition of function or activity (such as cell proliferation), as well as enhancement of function or activity.

The phrase "pharmaceutically acceptable" is recognized in the art. In certain embodiments, the term is free of composition, excipients, adjuvants, polymers, and within the scope of correct medical judgment, without excessive toxicity, irritation, allergic response, or other problems or complications. Includes other materials and / or dosage forms suitable for use in contact with human and animal tissues, commensurate with a reasonable benefit / risk ratio.

"Pharmaceutically acceptable salts" or "salts" are used herein to refer to acid or base salts that are suitable for or compatible with the treatment of patients.

As used herein, the term "pharmaceutically acceptable acid addition salt" means a non-toxic organic or inorganic salt of any base compound represented by Formula I. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and metal salts such as disodium hydrogen orthorate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include glycolic acid, lactic acid, pyruvate, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartrate acid, citric acid, ascorbic acid, maleic acid, benzoic acid. , Mono-, di- and tricarboxylic acids such as phenylacetic acid, cinnamic acid and salicylic acid, and sulfonic acids such as p-toluene sulfonic acid and methane sulfonic acid. Either monorates or dihydrates can be formed and such salts can be present in either hydrated, solvated or substantially anhydrous forms. In general, the acid addition salts of the compounds of formula I are soluble in water and various hydrophilic organic solvents and generally exhibit a higher melting point compared to their free base form. The choice of suitable salt is known to those of skill in the art. Other pharmaceutically unacceptable salts, such as oxalate, are of compounds of formula I, for example, for laboratory use or for subsequent conversion to pharmaceutically acceptable acid addition salts. Can be used in isolation.

As used herein, the term "pharmaceutically acceptable basic addition salt" refers to any non-toxic organic or inorganic base addition salt of any acidic compound of formula I or an intermediate thereof. means. Exemplary inorganic bases that form suitable salts include lithium hydroxide, sodium, potassium, calcium, magnesium, or barium. Exemplary organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The choice of suitable salt is known to those of skill in the art.

Therapeutic Methods Methods for treating elastic fiber-related disorders are provided herein. In certain embodiments, the present disclosure provides a method of treating elastic fiber-related disorders by administering a dose of a low molecular weight hyaluronic acid inhalation solution. Non-limiting examples of elastic fiber-related disorders include cutis laxa, Williams syndrome, α-1 antitrypsin deficiency (elastin excessively decomposes elastin), emphysema, liver disease, Buschke-Ollendorff syndrome, Menkes. Includes disease, elastic fibrous pseudoxanthoma, Marfan syndrome, Harler's disease, hypertension and congenital heart defects.

The present invention is generally described and will be more easily understood by reference to the following examples, but these are solely for the purpose of exemplifying specific embodiments and embodiments of the invention. It is included and is not intended to limit the invention.

Example 1: Assess the therapeutic role of HA
To assess the therapeutic role of HA, a 2-week, randomized, double-blind, placebo-controlled, phase 2a safety study was conducted in 11 COPD patients. The main objectives of this study are 1) to clarify the safety of repeated administration of HA to subjects with smoking-related COPD, and 2) the effect of HA on elastin degradation with cross-linked amino acids found only in this protein. It was to be measured and evaluated by the sputum and plasma concentrations of certain desmosine and isodesmosine (DID). This result indicates that inhalation of HA is well tolerated and rapidly reduces the destruction of pulmonary elastic fibers, thus supporting longer-term studies of the clinical efficacy of this drug. Is.

Clinical trial protocol
Eleven patients were recruited from two institutions. The breakdown was nine from Research Associates in Tuxon, Arizona, and two from St Luke's-Roosevelt Hospital Pulmonary Disease Center in New York. This study (NCT00993707) was conducted based on IND No. 70299 with the approval of the institutional clinical trial review committees of both organizations, and complied with the criteria of "Criteria for conducting clinical trials of pharmaceutical products".

Patients aged 40-76 years, with moderate airway obstruction (1 second effort expiratory volume> 40% of predicted), and GOLD grades 2 and 3 with a smoking history of at least 10 pack-years It met the diagnostic criteria for COPD (Table 1). Ten were Caucasian and one was African-American. Informed consent was obtained from all participants.

None of the patients were actively smoking at the time of recruitment and had quit smoking at least one year before the trial. Patients were randomly assigned to receive either 0.01% HA BID (8 patients) or the corresponding placebo (3 patients). All patients were instructed to continue conventional bronchodilator therapy during the trial.

Each patient self-administered 3 mL of aerosolized inhaled solution twice daily for 14 days using a Pari nebulizer. The primary safety end points were oxygen saturation, spirometry, spirometry, physical examination, vital signs, electrocardiogram, and laboratory evaluation (complete blood count, blood biochemical test, urinalysis). rice field. In addition, sputum and plasma DID concentrations were measured prior to treatment with either HA or placebo and remeasured at weekly intervals, including 1 week after treatment.

The treatment agent used for the HA preparation test consisted of 0.01% HA (150 kDa weight average molecular weight) isolated from Streptococcus equi; dissolved in 3 mL of isotonic buffered saline; plastic vial under sterile conditions. Wrapped in. The placebo consisted of a similarly packaged isotonic buffered saline solution that did not contain HA.

Measurement of DID sample The sample was combined with an equal volume of 37% HCl, hydrolyzed at 110 ° C. for 24 hours, then dried under vacuum and suspended in 2 mL butanol, acetic acid, and water (4: 1: 1). It was applied to a CF1 column, washed and eluted. DID separation was performed using a combination of mobile phases using a 2 x 100 mm dC18 column (Waters Corporation, Milford, MA, USA): 1) 7 mM heptafluorobutyric acid and 5 mM ammonium acetate in water, And 2) 5 mM ammonium acetate in 7 mM heptafluorobutyric acid and 80% acetonitrile. Elution gradients are linearly programmed from 100% A to 90% A at 10 minute intervals, and the separated crosslinks use a selected reaction monitoring of mass-to-charge ratio transitions with a TSQ Discovery electrospray tandem mass spectrometer ( Analyzed by Thermo Fisher Scientific, Waltham, MA, USA). Results were quantified by comparison with an external d4-labeled desmosine standard and sputum results were normalized to total protein as measured by the Micro BCATM assay kit (Thermo Fisher Scientific, Springfield Township, NJ, USA). bottom.

Statistical analysis
A statistically significant correlation (p <0.05) between DID levels and the length of time after treatment was determined by performing a two-sided t-test against the Pearson coefficient (r). Results were expressed as mean ± standard error of mean mean DID concentrations in plasma and sputum, and mean ± standard deviation of all other measurements.

Safety evaluation
HA administration had no significant effect on spirometry, lung volume, electrocardiogram, or hematological indicators. In particular, in the measurement of forced expiratory volume for 1 second, no significant change was observed during the test period with an interval of 1 week after the treatment (Table 2). Similarly, carbon monoxide diffusivity remained unchanged during the two-week study (Table 3). Adverse events were generally mild and recurred more frequently in the placebo group (Table 4). Nothing was directly attributed to the inhalation procedure.

Biomarker measurement
The HA group showed a tapering of plasma DID levels over the first 3 weeks of treatment (r = -0.98; p = 0.02; Figure 1). In contrast, there was no significant reduction in the placebo group (r = -0.70; p = 0.30). Sputum DID levels, which specifically reflect pulmonary elastin degradation, also showed tapering over the same time interval (r = -0.97; p = 0.03; Figure 2).

Example 2: Assessing the therapeutic role of HA Randomized double-blind to further evaluate the safety and efficacy of repeated doses of hyaluronic acid inhalation in patients with emphysema with alpha-1 antitrypsin deficiency Conduct a placebo-controlled phase 2 safety study. The purpose of this study is to establish the concentrations of desmosine and isodesmosine in plasma, sputum and urine, which are mainly measured systemically as markers of elastin degradation in the lung and also as markers of inflammation and fibrinogen. ..

HA drug preparation: hyaluronic acid inhalation solution The therapeutic agent (hyaluronic acid) used in the study consists of 0.03% hyaluronic acid dissolved in 3 ml of inhalation solution and is administered twice daily. Placebo consists of an HA-free inhalation solution.

Inclusion Criteria:
Men or women aged 18-80 years with consent, diagnosis of emphysema during screening according to National Institute of Health Guidelines 19 GOLD COPD classification stage I, II or III, evidence of emphysema on radiographic images, bronchial dilatation during screening Ratio of pre-drug FEV1 to forced emphysema (FVC) ≤80%, predicted normal values at screening FEV1 ≥30% and ≤79% (after bronchial dilator), laboratory tests (whole blood cell count, blood biochemical test, Evidence of alpha-1 antitrypsin deficiency (AATD) with a genotype other than PiMZ deficiency, whether the urine test) is within the normal range, or clinically acceptable to PI and sponsors at the time of screening, patients Must discontinue use of intravenous alpha-1 antitrypsin protein (AAT) augmentation therapy at least 3 months before entering the study.

Reference Incorporation All publications and patents referred to herein are by reference in their entirety, as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. Incorporated herein. In the event of inconsistency, the present application will prevail, including the definitions herein.

Equivalents Although specific embodiments of the present invention have been discussed, the above specification is exemplary and not limiting. Many variations of the present invention will become apparent to those skilled in the art by examining the specification and the claims below. The full scope of the invention should be determined by reference to the claims, the full range of their equivalents, and the specification, as well as such variations.

Claims (17)

Hyaluronic acid or a pharmaceutically acceptable salt thereof having a weight average molecular weight (M _{w) of about 50 to about 1000 kDa; and a pharmaceutically acceptable excipient.}
Pharmaceutical composition containing: The pharmaceutical composition according to claim 1, wherein the hyaluronic acid has a weight average molecular weight (M _{w) of about 150 kDa.} The pharmaceutical composition according to claim 1 or 2, which is in a form suitable for inhalation. The pharmaceutical composition according to any one of claims 1 to 3, which is in a form suitable for intranasal, intrapulmonary, tracheal, intrabronchial, or intraalveolar administration. The pharmaceutical composition according to claim 4, which is in a form suitable for intra-alveolar administration. The pharmaceutical composition according to any one of claims 1 to 5, which is in a form suitable for administration by a dry powder inhaler. The pharmaceutical composition according to any one of claims 1 to 5, which is in a form suitable for administration by a liquid spray device. The pharmaceutical composition according to claim 7, wherein the liquid spraying device is an aerosol device. The pharmaceutical composition according to claim 8, wherein the aerosol device is a nebulizer or an electrohydrodynamic aerosol device. An inhaler comprising the pharmaceutical composition according to any one of claims 1 to 6. The inhaler according to claim 10, wherein the inhaler is configured to deliver droplets having a size of about 2 μm to about 3 μm. A method for treating elastic fiber-related disorders in a subject, comprising administering to the subject hyaluronic acid having a weight average molecular weight (M _{w) of about 50 to about 1000 kDa or a pharmaceutically acceptable salt thereof.} The method of claim 12, wherein the hyaluronic acid has a weight average molecular weight (M _{w) of about 150 kDa.} The method of claim 12 or 13, comprising administering hyaluronic acid by inhalation. The method of any one of claims 12-14, comprising administering hyaluronic acid to the sinuses, pulmonary system, trachea, bronchi, or alveoli. Elastic fiber-related disorders include cutis laxa, Williams syndrome, alpha-1 antitrypsin deficiency, emphysema, chronic obstructive pulmonary disease (COPD), liver disease, Buschke-Ollendorff syndrome, Menquez disease, elastic fibrous pseudoyellow tumor, The method according to any one of claims 12 to 15, which is Marfan syndrome, Harler's disease, hypertension or congenital heart defect. 16. The method of claim 16, wherein the elastic fiber-related disorder is COPD.

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